Neoplasia: core concepts

Hamartomas and choristomas are tumor-like growths thought to be the result of developmental
anomalies. They are NOT true neoplasms (ie, they do not show continuous excessive growth. The
tumors are abnormal, disorgani!ed, proliferating masses of several different adult cell types.
" hamartoma is composed of tissues that are normally present in the organ in which the tumor arises# a
hamartoma of the lung consists of a disorganized mass of bronchial epithelium and cartilage that
may become so large that it presents as a lung mass. $ts growth is coordinated with that of the lung
itself.
" choristoma resembles a hamartoma but contains tissues that are NOT normally present in its site of
origin. " disorderly mass of smooth muscle and pancreatic acini and ducts in the wall of the stomach is
properly called a choristoma. " gastric choristoma such as this may present as an intramural mass that is
clinically indistinguishable from a benign neoplasm.
" benign epithelial neoplasm is called an adenoma if it arises within a gland (eg, thyroid adenoma,
colonic adenoma or a papilloma when arising from an epithelial surface. %apillomas may arise from
s&uamous, glandular, or transitional epithelium (eg, s&uamous papilloma, intraductal papilloma of the
breast, and transitional cell papilloma, respectively.
-Malignant epithelial neoplasms are called carcinomas (adenocarcinomas if derived from glandular
epithelia# s&uamous carcinoma and transitional cell carcinoma if originating in those kinds of
epithelia.
Benign mesenchymal neoplasms are named after the cell of origin (a 'reek or (atin word is used
followed by the suffix -oma (Table )*-+. The names of these tumors may contain the organ of origin
and an ad,ective, eg, cavernous hemangioma of the liver
Malignant mesenchymal neoplasms are named after the cell of origin, to which is added the suffix
-sarcoma. "gain, ad,ectives are commonly used# liposarcomas are classified as sclerosing, myxoid,
round cell, or pleomorphic
Mixed Tumors: Neoplasms composed of more than one neoplastic cell type are called mixed tumors.
-alignant mixed tumors may have two epithelial components, as in adenos&uamous carcinoma# two
mesenchymal components, as in malignant fibrous histiocytoma# or an epithelial and a mesenchymal
component, as in carcinosarcoma of the lung and malignant mixed m.llerian tumor of the uterus
Mechanisms and Causes
Intro: Neoplasia is an abnormality of cell growth and
multiplication characterized by the following features: (1)
excessive cellular proliferation that typically produces an
abnormal mass, or tumor; (2) uncoordinated growth
occurring without any apparent purpose; and (3)
persistence of excessive cell proliferation and growth
even after the inciting stimulus that evoked the change
has been removedie, neoplasia is an irreversible
process.
Origin of tumor:
Monoclonal: the initial neoplastic change affects a single
cell, which then multiplies and gives rise to the neoplasm.
Example: neoplasms of B lymphocytes (B-cell lymphomas
and plasma-cell myelomas) that produce immunoglobulin.
-REMEMBER: as a neoplasm progresses, further
subclones may evolve from the initial clone as a result
of additional ongoing genetic changes (multiple hits)
Field origin: A carcinogenic agent acting on a large
number of similar cells may produce a field of potentially
neoplastic cells. Neoplasms may then arise from one or
more cells within this field. In many cases the result is
several discrete neoplasms, each of which derives from a
separate clonal precursor. The field change may be
regarded as the first of 2 or more sequential steps that
lead to overt cancer.
Multiple Hits
Theory that carcinogenesis re&uires two hits. The first event is initiation, with the carcinogen causing it
called the initiator. The second event, which induces neoplastic growth, is promotion, and the agent is
the promoter. $t is now believed that in fact multiple hits occur (five or more, that multiple factors may
cause these hits, and that each hit produces a change in the genome of the affected cell that is
transmitted to its progeny (ie, the neoplastic clone.
-another way to put it - 'enetic predisposition / )
st
hit, then a somatic mutation (due to, for
example, a carcinogen provides the 0
nd
hit
-another example1 Oncogenesis in 2urkitt3s lymphoma. The )st hit is infection of 2 lymphocytes
with 4pstein-2arr virus. 5hronic malaria induces proliferation of 2 lymphocytes, increasing the
likelihood of the 0nd hit, which is a chromosomal translocation that activates a cellular oncogene and
leads to malignant lymphoma.
Oncogenes and tumor suppressor genes
There are two main categories of genes that regulate cell growth, and the abnormal action of either or
both may lead to neoplasia. roto!oncogenes "cellular oncogenes: c! onc # code for a variety of growth
factors, receptors, and signal-relay or transcription factors, which act in concert to control entry into the
cell cycle (eg, the growth promoter effect. The action of these genes is opposed by the action of tumor
suppressor genes, which serve to down-regulate the cell cycle. " net increase in the production of
stimulatory (promoter factors, a decrease in inhibitory (suppressor growth factors, or the production of
functionally abnormal factors may lead to uncontrolled cell growth.
The neoplastic cell is then the result of several such changes interacting in summative fashion (multiple
hits. 6its may result from inherited genetic abnormalities, spontaneous mutations, or the actions of
external agents that may affect the gene. These mutagens include chemical carcinogens, ioni!ing
radiation, and viruses (which introduce new 7N". The effect of these agents is exacerbated by
incompetent 7N" repair mechanisms such as mutation of the genes that monitor 7N" duplication.
7efective repair is common in peeps with certain inherited conditions (such as xeroderma pigmentosum
8sunlight# skin cancer9. $n dudes with these conditions, a first hit (eg, defective repair mechanisms is
inherited and is already present in every cell in the body.
Mechanisms of gene acti$ation and inacti$ation
Neoplastic transformation occurs as a result of activation (or :derepression; of growth promoter genes
(proto!oncogenes or inactivation or loss of suppressor genes. %cti$ation is a functional concept where
the normal action of growth regulation is diverted into oncogenesis. The resultant activated proto-
oncogene is referred to as an acti$ated oncogene (or a mutant oncogene, if structurally changed.
"ctivation and inactivation may occur through several mechanisms1
() mutation, including single nucleotide loss (frameshift or substitution (nonsense or missense codon,
codon loss, gene deletion or more ma,or chromosomal loss
(0 translocation to a different part of the genome where regulatory influences may favor inappropriate
expression or repression
(< insertion of an oncogenic virus at an ad,acent site
(+ amplification (production of multiple copies of the proto-oncogenes, which appear as additional
chromosome bands or extra 7N" fragments (double minutes
(= introduction of viral oncogenes
(> derepression (loss of suppressor control.
?ee lecture slides for summary of agents causing neoplasms (i.e. carcinogens - she actually wasn@t
terrible at that part
Biological and clinical effects of neoplasias
roducts&mar'ers of neoplasias
). (nzymes: 4levated serum levels of prostate!specific acid phosphatase occur in prostate cancer,
usually when invasion has occurred beyond the capsule of the gland. -easurement of prostate-
specific epithelial antigen (%?" is more sensitive and has found use as a screening test in older
men.
0. (xcessi$e Hormone )ecretion: Aell-differentiated neoplasms of endocrine cells are fre&uently
associated with excessive production of hormones. Overproduction is due not only to the increased
number of cells caused by the tumor but also to a failure of normal control mechanisms. The
resulting clinical symptoms are readily predictable because they represent the manifestations of
excess hormone levels.
0.). 4xample1 '6, prolactin, "5T6 in pituitary adenoma
%bnormal differentiation and anaplasia
Ahen benign or slow-growing malignant neoplastic cells proliferate, they tend to differentiate normally
and resemble their normal counterparts (ie, they are well-differentiated. Bor example, the cells
constituting a lipoma resemble mature adipocytes on microscopic examination.
"s the degree of malignancy increases, the degree of differentiation decreases, and neoplastic cells do
not resemble the cell of origin so closely. Ahen the cell of origin cannot be recogni!ed on microscopic
examination, it is dubbed undifferentiated or anaplastic.
-"naplastic cells display marked pleomorphism. The nuclei are characteristically extremely
hyperchromatic (darkly stained and large. The nuclear-cytoplasmic ratio may approach )1)
instead of the normal )1+ or )1>. 'iant cells that are considerably larger than their neighbors may
be formed and possess either one enormous nucleus or several nuclei (syncytia. "naplastic
nuclei are variable and bi!arre in si!e and shape. The chromatin is coarse and clumped, and
nucleoli may be of astounding si!e. -ore important, mitoses are often numerous and distinctly
atypical. "lso, anaplastic cells usually fail to develop recogni!able patterns of orientation to one
another (i.e. they lose normal polarity. They may grow in sheets, with total loss of communal
structures, such as gland formation or stratified s&uamous architecture. "naplasia is the most
extreme disturbance in cell growth encountered in the spectrum of cellular proliferations.
-Metaplasia: Neoplastic cells may occasionally differentiate in a manner that is abnormal for
the cell of origin. Bor example, neoplastic endometrial glandular epithelium sometimes
differentiates to form both glandular and s&uamous epithelial cells (adenos&uamous carcinoma.
To put it another way, metaplasia is the reversible replacement of one differentiated cell type
with another mature differentiated cell type. This is often due to an abnormal stimulus, forcing
the cells to convert into a different type which is better suited for the situation.
*n$asion&*nfiltration
5arcinomas and sarcomas demonstrate similar patterns of invasion despite their different tissues of
origin. $nvasion of the basement membrane by carcinoma distinguishes invasive cancer from
intraepithelial (i.e. carcinoma in situ cancer. 6aving penetrated (haha, penetrated the basement
membrane, malignant cells gain access to the lymphatics and blood vessels, the first step toward general
dissemination (Bigure )C-)D. $nfiltrating neoplastic cells tend to follow fascial planes along the
pathway of least resistance# eventually, destruction of tissue occurs. The mechanisms whereby
neoplastic cells invade and destroy tissues are poorly understood, but protease production, loss of
contact inhibition of neoplastic cells, and decreased cell adhesiveness are believed to play a part.
?o, to sum up the se&uence of events1
E +ysplasia is the earliest form of pre-cancerous lesion recogni!able in a pap smear or biopsy.
7ysplasia can be low grade or high grade. The risk of low grade dysplasia transforming into high
grade dysplasia, and eventually cancer, is low. Treatment is usually straightforward. 6igh grade
dysplasia represents a more advanced progression towards malignant transformation.
E ,arcinoma in situ represents the transformation of a neoplastic lesion to one in which cells
undergo essentially no maturation, and thus may be considered :cancer-like;. $n this state,
epithelial cells have lost their tissue identity and have reverted back to a primitive cell form that
grows rapidly and without regulation. 6owever, this form of cancer remains localized, and has
-OT in$aded past the basement membrane.
E *n$asi$e carcinoma is the final step in this se&uence. $t is a cancer which has invaded beyond the
basement membrane and has potential to metastasi!e.
.ymphatic Metastasis
-etastasis via the lymphatics occurs early in carcinomas and melanomas but is an unusual occurrence in
most sarcomas, which tend to spread mainly via the bloodstream
Hematogenous Metastasis
4ntry of cancerous cells into the bloodstream tends to occur during the early clinical course. -ost of
these malignant cells are thought to be destroyed by the immune system, but some become coated with
fibrin and entrapped in capillaries. -etastasis can occur only if enough cancerous cells survive in the
tissues to become established and proliferate at a second site. %roduction of tumor angiogenesis factor
(T%/ by the cancerous cells stimulates growth of new capillaries in the vicinity of tumor cells and
encourages vasculari!ation of the growing metastasis.
0rade $s. )tage
0rade1 the degree of cellular differentiation. " low grade is well differentiated, a high grade is
poorlyFundifferentiated.
)tage1 the extent of spread of a neoplasm# pathologic stage is determined by the extent of infiltration
and metastasis (eg, depth of invasion of the wall of a viscus# lymph node, bone marrow, or organ
involvement. 7escribed using T-M classification, which classifies neoplasms on the basis of size of
the primary tumor (T, lymph node involvement (N, and distant metastases (-.